Eosinophils and tissue remodeling: Relevance to airway disease
Authors: Salman Siddiqui, Claus Bachert, Leif Bjermer, Kathleen M. Buchheit, Mario Castro, Yimin Qin, Hitasha Rupani, Hironori Sagara, Peter Howarth, Camille Taillé
Journal: Journal of Allergy and Clinical Immunology (2023)

The ability of human tissue to reorganize and restore its existing structure underlies tissue homeostasis in the healthy airways, but in disease can persist without normal resolution, leading to an altered airway structure. Eosinophils play a cardinal role in airway remodeling both in health and disease, driving epithelial homeostasis and extracellular matrix turnover. Physiological consequences associated with eosinophil-driven remodeling include impaired lung function and reduced bronchodilator reversibility in asthma, and obstructed airflow in chronic rhinosinusitis with nasal polyps. Given the contribution of airway remodeling to the development and persistence of symptoms in airways disease, targeting remodeling is an important therapeutic consideration. Indeed, there is early evidence that eosinophil attenuation may reduce remodeling and disease progression in asthma. This review provides an overview of tissue remodeling in both health and airway disease with a particular focus on eosinophilic asthma and chronic rhinosinusitis with nasal polyps, as well as the role of eosinophils in these processes and the implications for therapeutic interventions. Areas for future research are also noted, to help improve our understanding of the homeostatic and pathological roles of eosinophils in tissue remodeling, which should aid the development of targeted and effective treatments for eosinophilic diseases of the airways. The ability of human tissue to reorganize and restore its existing structure underlies tissue homeostasis in the healthy airways, but in disease can persist without normal resolution, leading to an altered airway structure. Eosinophils play a cardinal role in airway remodeling both in health and disease, driving epithelial homeostasis and extracellular matrix turnover. Physiological consequences associated with eosinophil-driven remodeling include impaired lung function and reduced bronchodilator reversibility in asthma, and obstructed airflow in chronic rhinosinusitis with nasal polyps. Given the contribution of airway remodeling to the development and persistence of symptoms in airways disease, targeting remodeling is an important therapeutic consideration. Indeed, there is early evidence that eosinophil attenuation may reduce remodeling and disease progression in asthma. This review provides an overview of tissue remodeling in both health and airway disease with a particular focus on eosinophilic asthma and chronic rhinosinusitis with nasal polyps, as well as the role of eosinophils in these processes and the implications for therapeutic interventions. Areas for future research are also noted, to help improve our understanding of the homeostatic and pathological roles of eosinophils in tissue remodeling, which should aid the development of targeted and effective treatments for eosinophilic diseases of the airways. Human tissue has an inherent ability to reorganize or restore its existing structure, so-called tissue remodeling, which enables normal development and growth and mediates responses to injury or inflammation. Increasing evidence demonstrates that both the upper and lower airways can respond to injury by repairing and replacing damaged tissue through processes including extracellular matrix (ECM) deposition and degradation and epithelial cell migration.1Samitas K. Carter A. Kariyawasam H.H. Xanthou G. Upper and lower airway remodelling mechanisms in asthma, allergic rhinitis and chronic rhinosinusitis: the one airway concept revisited.Allergy. 2018; 73: 993-1002Crossref PubMed Scopus (141) Google Scholar While in healthy tissue this remodeling process contributes to damage repair and growth, airway disease can occur where the same process is exaggerated and persists without normal resolution.1Samitas K. Carter A. Kariyawasam H.H. Xanthou G. Upper and lower airway remodelling mechanisms in asthma, allergic rhinitis and chronic rhinosinusitis: the one airway concept revisited.Allergy. 2018; 73: 993-1002Crossref PubMed Scopus (141) Google Scholar,2Chung K.F. Godard P. Adelroth E. Ayres J. Barnes N. Barnes P. et al.Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society.Eur Respir J. 1999; 13: 1198-1208PubMed Google Scholar As the structural changes associated with airway remodeling develop during the course of disease, airway function often declines and the response to standard therapy becomes poor.2Chung K.F. Godard P. Adelroth E. Ayres J. Barnes N. Barnes P. et al.Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society.Eur Respir J. 1999; 13: 1198-1208PubMed Google Scholar Eosinophils are known historically as end-stage effectors in the inflammatory response to infection and in eosinophilic diseases such as eosinophilic asthma.3Long H. Liao W. Wang L. Lu Q. A player and coordinator: the versatile roles of eosinophils in the immune system.Transfus Med Hemother. 2016; 43: 96-108Crossref PubMed Scopus (56) Google Scholar Now, as proposed over 10 years ago by Lee et al4Lee J.J. Jacobsen E.A. McGarry M.P. Schleimer R.P. Lee N.A. Eosinophils in health and disease: the LIAR hypothesis.Clin Exp Allergy. 2010; 40: 563-575Crossref PubMed Scopus (263) Google Scholar with the local immunity and/or remodeling/repair hypothesis, eosinophils are also recognized as essential contributors to tissue homeostasis, repair, and remodeling.5Chusid M.J. Eosinophils: friends or foes?.J Allergy Clin Immunol Pract. 2018; 6: 1439-1444Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Here, we review evidence for the role of eosinophils in tissue repair and remodeling in health and in airway disease. We focus on data from studies in severe eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), 2 of the most studied eosinophilic airway diseases for which biologic treatments have been approved. Data from patients with these conditions, which are associated with substantial morbidity and in some cases an unmet treatment need, have provided valuable insights into the role of eosinophils in human airways, validating earlier murine model data.6Lee J.J. Jacobsen E.A. Ochkur S.I. McGarry M.P. Condjella R.M. Doyle A.D. et al.Human versus mouse eosinophils: "that which we call an eosinophil, by any other name would stain as red".J Allergy Clin Immunol. 2012; 130: 572-584Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 7Lee J.J. Dimina D. Macias M.P. Ochkur S.I. McGarry M.P. O'Neill K.R. et al.Defining a link with asthma in mice congenitally deficient in eosinophils.Science. 2004; 305: 1773-1776Crossref PubMed Scopus (643) Google Scholar, 8Tanaka H. Komai M. Nagao K. Ishizaki M. Kajiwara D. Takatsu K. et al.Role of interleukin-5 and eosinophils in allergen-induced airway remodeling in mice.Am J Respir Cell Mol Biol. 2004; 31: 62-68Crossref PubMed Scopus (161) Google Scholar, 9Abdala-Valencia H. Coden M.E. Chiarella S.E. Jacobsen E.A. Bochner B.S. Lee J.J. et al.Shaping eosinophil identity in the tissue contexts of development, homeostasis, and disease.J Leukoc Biol. 2018; 104: 95-108Crossref PubMed Scopus (82) Google Scholar, 10Khan A. Huynh T.M.T. Vandeplas G. Joish V.N. Mannent L.P. Tomassen P. et al.The GALEN rhinosinusitis cohort: chronic rhinosinusitis with nasal polyps affects health-related quality of life.Rhinology. 2019; 57: 343-351PubMed Google Scholar, 11Busse W.W. Kraft M. Current unmet needs and potential solutions to uncontrolled asthma.Eur Respir Rev. 2022; 31210176Crossref Scopus (13) Google Scholar During normal airway tissue development and growth, or in response to injury and/or inflammation, various structural adaptations contribute to repair and regeneration.12Fehrenbach H. Wagner C. Wegmann M. Airway remodeling in asthma: what really matters.Cell Tissue Res. 2017; 367: 551-569Crossref PubMed Scopus (253) Google Scholar Tissue repair is driven by epithelial cell migration to the site of damage and deposition of a provisional matrix comprising ECM glycoproteins including fibronectin and vitronectin, as well as basement membrane components such as laminin and collagen IV (Fig 1).12Fehrenbach H. Wagner C. Wegmann M. Airway remodeling in asthma: what really matters.Cell Tissue Res. 2017; 367: 551-569Crossref PubMed Scopus (253) Google Scholar, 13Reeves S.R. Kolstad T. Lien T.Y. Elliott M. Ziegler S.F. Wight T.N. et al.Asthmatic airway epithelial cells differentially regulate fibroblast expression of extracellular matrix components.J Allergy Clin Immunol. 2014; 134: 663-670.e1Abstract Full Text Full Text PDF PubMed Google Scholar, 14Fang C.L. Yin L.J. Sharma S. Kierstein S. Wu H.F. Eid G. et al.Resistin-like molecule-beta (RELM-beta) targets airways fibroblasts to effect remodelling in asthma: from mouse to man.Clin Exp Allergy. 2015; 45: 940-952Crossref PubMed Google Scholar, 15Acharya K.R. Ackerman S.J. Eosinophil granule proteins: form and function.J Biol Chem. 2014; 289: 17406-17415Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar, 16Barker T.H. Engler A.J. The provisional matrix: setting the stage for tissue repair outcomes.Matrix Biol. 2017; 60-61: 1-4Crossref PubMed Scopus (103) Google Scholar, 17Vatrella A. Maglio A. Pelaia C. Ciampo L. Pelaia G. Vitale C. Eosinophilic inflammation: an appealing target for pharmacologic treatments in severe asthma.Biomedicines. 2022; 10: 2181Crossref Scopus (4) Google Scholar In addition, underlying mesenchymal cells secrete ECM proteins and cytokines that contribute to airway repair and stimulate epithelial cell functions.18Sacco O. Silvestri M. Sabatini F. Sale R. Defilippi A.C. Rossi G.A. Epithelial cells and fibroblasts: structural repair and remodelling in the airways.Paediatr Respir Rev. 2004; 5: S35-40Crossref PubMed Scopus (85) Google Scholar The spreading, migration, and proliferation of epithelial cells during epithelial repair requires the participation of integrins, which signal through matrix metalloproteinase (MMP)-dependent activation of TGF-β, a multipotent epithelial and mesenchymal cell growth factor.19Legrand C. Gilles C. Zahm J.M. Polette M. Buisson A.C. Kaplan H. et al.Airway epithelial cell migration dynamics. MMP-9 role in cell-extracellular matrix remodeling.J Cell Biol. 1999; 146: 517-529Crossref PubMed Scopus (218) Google Scholar, 20Crosby L.M. Waters C.M. Epithelial repair mechanisms in the lung.Am J Physiol Lung Cell Mol Physiol. 2010; 298: L715-L731Crossref PubMed Scopus (527) Google Scholar, 21Neurohr C. Nishimura S.L. Sheppard D. Activation of transforming growth factor-beta by the integrin alphavbeta8 delays epithelial wound closure.Am J Respir Cell Mol Biol. 2006; 35: 252-259Crossref PubMed Scopus (0) Google Scholar Following airway injury, epithelial cells are also regulated by WNT/β-catenin signaling pathways, which play critical roles in the function and behavior of these cells during tissue regeneration.22Hachim M.Y. Elemam N.M. Ramakrishnan R.K. Bajbouj K. Olivenstein R. Hachim I.Y. et al.Wnt signaling is deranged in asthmatic bronchial epithelium and fibroblasts.Front Cell Dev Biol. 2021; 9641404Crossref Scopus (11) Google Scholar, 23Kim H.T. Yin W. Nakamichi Y. Panza P. Grohmann B. Buettner C. et al.WNT/RYK signaling restricts goblet cell differentiation during lung development and repair.Proc Natl Acad Sci U S A. 2019; 116: 25697-25706Crossref Scopus (22) Google Scholar, 24Song J. Zhu X.M. Wei Q.Y. MSCs reduce airway remodeling in the lungs of asthmatic rats through the Wnt/beta-catenin signaling pathway.Eur Rev Med Pharmacol Sci. 2020; 24: 11199-11211Google Scholar Resolution of inflammation and tissue repair in healthy tissue requires the clearance of activated immune cells and production of lipid pro-resolving mediators that contribute to normal tissue restoration.25Sugimoto M.A. Sousa L.P. Pinho V. Perretti M. Teixeira M.M. Resolution of inflammation: what controls its onset?.Front Immunol. 2016; 7: 160Crossref PubMed Scopus (384) Google Scholar Pathological airway remodeling is primarily considered a consequence of chronic injury and/or inflammation that leads to persistently altered airway wall structure and function.26Grainge C.L. Lau L.C. Ward J.A. Dulay V. Lahiff G. Wilson S. et al.Effect of bronchoconstriction on airway remodeling in asthma.N Engl J Med. 2011; 364: 2006-2015Crossref PubMed Scopus (442) Google Scholar Some studies (reviewed by Fehrenbach et al12Fehrenbach H. Wagner C. Wegmann M. Airway remodeling in asthma: what really matters.Cell Tissue Res. 2017; 367: 551-569Crossref PubMed Scopus (253) Google Scholar) also report that airway features of remodeling in symptomatic children may be evident before a clinical diagnosis of asthma is made, and it is appreciated that mechanical stress, in the absence of inflammation, may promote tissue remodeling.12Fehrenbach H. Wagner C. Wegmann M. Airway remodeling in asthma: what really matters.Cell Tissue Res. 2017; 367: 551-569Crossref PubMed Scopus (253) Google Scholar Primarily, the remodeling changes arise from dysregulated repair and regeneration pathways, leading to an exaggerated wound repair response culminating in the accumulation of (myo)fibroblasts and increased ECM deposition (Fig 1).12Fehrenbach H. Wagner C. Wegmann M. Airway remodeling in asthma: what really matters.Cell Tissue Res. 2017; 367: 551-569Crossref PubMed Scopus (253) Google Scholar, 13Reeves S.R. Kolstad T. Lien T.Y. Elliott M. Ziegler S.F. Wight T.N. et al.Asthmatic airway epithelial cells differentially regulate fibroblast expression of extracellular matrix components.J Allergy Clin Immunol. 2014; 134: 663-670.e1Abstract Full Text Full Text PDF PubMed Google Scholar, 14Fang C.L. Yin L.J. Sharma S. Kierstein S. Wu H.F. Eid G. et al.Resistin-like molecule-beta (RELM-beta) targets airways fibroblasts to effect remodelling in asthma: from mouse to man.Clin Exp Allergy. 2015; 45: 940-952Crossref PubMed Google Scholar In asthma, ECM deposition is increased in the reticular basement membrane region, lamina propria, and submucosa, with deposited proteins including collagen (types I, III, and V), the adhesion proteins fibronectin and tenascin, plus proteoglycans that play roles in the interaction between fibrils and collagen fibrinogenesis, which are considered to be important in the functional consequences of the remodeling process.27Hough K.P. Curtiss M.L. Blain T.J. Liu R.M. Trevor J. Deshane J.S. et al.Airway remodeling in asthma.Front Med (Lausanne). 2020; 7: 191Crossref PubMed Scopus (157) Google Scholar, 28Roche W.R. Beasley R. Williams J.H. Holgate S.T. Subepithelial fibrosis in the bronchi of asthmatics.Lancet. 1989; 1: 520-524Abstract PubMed Scopus (985) Google Scholar, 29Royce S.G. Cheng V. Samuel C.S. Tang M.L. The regulation of fibrosis in airway remodeling in asthma.Mol Cell Endocrinol. 2012; 351: 167-175Crossref PubMed Scopus (90) Google Scholar, 30Ito J.T. Lourenco J.D. Righetti R.F. Tiberio I. Prado C.M. Lopes F. Extracellular matrix component remodeling in respiratory diseases: what has been found in clinical and experimental studies?.Cells. 2019; 8: 342Crossref PubMed Scopus (82) Google Scholar Epithelial-mesenchymal transition, the transformation of epithelial cells into fibroblast-like mesenchymal cells due to loss of epithelial polarity and expression of mesenchymal proteins,31Pain M. Bermudez O. Lacoste P. Royer P.J. Botturi K. Tissot A. et al.Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype.Eur Respir Rev. 2014; 23: 118-130Crossref PubMed Scopus (145) Google Scholar, 32Ozdamar B. Bose R. Barrios-Rodiles M. Wang H.R. Zhang Y. Wrana J.L. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity.Science. 2005; 307: 1603-1609Crossref PubMed Scopus (740) Google Scholar, 33Hackett T.L. Warner S.M. Stefanowicz D. Shaheen F. Pechkovsky D.V. Murray L.A. et al.Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1.Am J Respir Crit Care Med. 2009; 180: 122-133Crossref PubMed Scopus (297) Google Scholar, 34Sun Z. Ji N. Ma Q. Zhu R. Chen Z. Wang Z. et al.Epithelial-mesenchymal transition in asthma airway remodeling is regulated by the IL-33/CD146 axis.Front Immunol. 2020; 11: 1598Crossref PubMed Scopus (30) Google Scholar, 35Chiarella E. Lombardo N. Lobello N. Aloisio A. Aragona T. Pelaia C. et al.Nasal polyposis: insights in epithelial-mesenchymal transition and differentiation of polyp mesenchymal stem cells.Int J Mol Sci. 2020; 21: 6878Crossref Scopus (5) Google Scholar contributes to accumulation of fibroblast-like cells. Moreover, fibroblast transformation into myofibroblasts further increases ECM deposition.36Larsen K. Tufvesson E. Malmstrom J. Morgelin M. Wildt M. Andersson A. et al.Presence of activated mobile fibroblasts in bronchoalveolar lavage from patients with mild asthma.Am J Respir Crit Care Med. 2004; 170: 1049-1056Crossref PubMed Scopus (48) Google Scholar,37Michalik M. Wojcik-Pszczola K. Paw M. Wnuk D. Koczurkiewicz P. Sanak M. et al.Fibroblast-to-myofibroblast transition in bronchial asthma.Cell Mol Life Sci. 2018; 75: 3943-3961Crossref PubMed Scopus (78) Google Scholar TGF-β mediates epithelial-mesenchymal transition33Hackett T.L. Warner S.M. Stefanowicz D. Shaheen F. Pechkovsky D.V. Murray L.A. et al.Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1.Am J Respir Crit Care Med. 2009; 180: 122-133Crossref PubMed Scopus (297) Google Scholar and stimulates fibroblasts to synthesize collagens types I and III, fibronectin, and proteoglycans.38Burgess J.K. Mauad T. Tjin G. Karlsson J.C. Westergren-Thorsson G. The extracellular matrix—the under-recognized element in lung disease?.J Pathol. 2016; 240: 397-409Crossref PubMed Scopus (161) Google Scholar TGF-β is activated by integrins, reactive oxygen species, and mechanical stress and stimulates downstream SMAD2/3 and SMAD4 signaling that mediate gene expression.39Ojiaku C.A. Yoo E.J. Panettieri Jr., R.A. Transforming growth factor beta1 function in airway remodeling and hyperresponsiveness. The missing link?.Am J Respir Cell Mol Biol. 2017; 56: 432-442Crossref Scopus (74) Google Scholar Increased levels of TGF-β are also associated with increased osteopontin, an ECM protein released by eosinophils that is implicated in the modulation of inflammation and fibrosis in diseased airways.40Arjomandi M. Frelinger J. Donde A. Wong H. Yellamilli A. Raymond W. Secreted osteopontin is highly polymerized in human airways and fragmented in asthmatic airway secretions.PLoS One. 2011; 6e25678Crossref Scopus (10) Google Scholar, 41Delimpoura V. Bakakos P. Tseliou E. Bessa V. Hillas G. Simoes D.C. et al.Increased levels of osteopontin in sputum supernatant in severe refractory asthma.Thorax. 2010; 65: 782-786Crossref PubMed Scopus (0) Google Scholar, 42Kaartinen M.T. Pirhonen A. Linnala-Kankkunen A. Maenpaa P.H. Cross-linking of osteopontin by tissue transglutaminase increases its collagen binding properties.J Biol Chem. 1999; 274: 1729-1735Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 43Kohan M. Bader R. Puxeddu I. Levi-Schaffer F. Breuer R. Berkman N. Enhanced osteopontin expression in a murine model of allergen-induced airway remodelling.Clin Exp Allergy. 2007; 37: 1444-1454PubMed Google Scholar, 44Kohan M. Breuer R. Berkman N. Osteopontin induces airway remodeling and lung fibroblast activation in a murine model of asthma.Am J Respir Cell Mol Biol. 2009; 41: 290-296Crossref PubMed Scopus (0) Google Scholar, 45Trinh H.K.T. Nguyen T.V.T. Kim S.H. Cao T.B.T. Luu Q.Q. Kim S.H. et al.Osteopontin contributes to late-onset asthma phenotypes in adult asthma patients.Exp Mol Med. 2020; 52: 253-265Crossref Scopus (10) Google Scholar Eosinophils are highly complex cells with a wide range of surface molecules and receptors. Key cell membrane receptors that define the unique biology of eosinophils include CCR3, which binds eotaxins, the lectin (carbohydrate-binding protein) Siglec-8, which can trigger eosinophil cell death when engaged, and IL-5RA.46Legrand F. Cao Y. Wechsler J.B. Zhu X. Zimmermann N. Rampertaap S. et al.Sialic acid-binding immunoglobulin-like lectin (Siglec) 8 in patients with eosinophilic disorders: receptor expression and targeting using chimeric antibodies.J Allergy Clin Immunol. 2019; 143: 2227-2237.e10Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar,47Rosenberg H.F. Dyer K.D. Foster P.S. Eosinophils: changing perspectives in health and disease.Nat Rev Immunol. 2013; 13: 9-22Crossref PubMed Scopus (624) Google Scholar Eosinophils also express receptors for multiple other cytokines and growth factors, including IL-4, IL-13, IL-33, thymic stromal lymphopoietin, and TGF-β.47Rosenberg H.F. Dyer K.D. Foster P.S. Eosinophils: changing perspectives in health and disease.Nat Rev Immunol. 2013; 13: 9-22Crossref PubMed Scopus (624) Google Scholar They also express integrin adhesion molecules, through which they can interact with endothelial and airway cells.48Barthel S.R. Johansson M.W. McNamee D.M. Mosher D.F. Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma.J Leukoc Biol. 2008; 83: 1-12Crossref PubMed Scopus (118) Google Scholar Eosinophils are equipped to modify their immediate tissue environment; they contain large specific cytoplasmic granules, which possess a crystalloid structure and can be released into target tissues on activation (Fig 1).15Acharya K.R. Ackerman S.J. Eosinophil granule proteins: form and function.J Biol Chem. 2014; 289: 17406-17415Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar Granules are released by cytolysis or piecemeal degranulation, during which granule proteins are packaged into secretory vesicles that deliver specific proteins to the extracellular space while leaving intracellular granules intact.49Weller P.F. Spencer L.A. Functions of tissue-resident eosinophils.Nat Rev Immunol. 2017; 17: 746-760Crossref PubMed Scopus (287) Google Scholar, 50Spencer L.A. Bonjour K. Melo R.C. Weller P.F. Eosinophil secretion of granule-derived cytokines.Front Immunol. 2014; 5: 496Crossref PubMed Scopus (96) Google Scholar, 51Melo R.C. Weller P.F. Piecemeal degranulation in human eosinophils: a distinct secretion mechanism underlying inflammatory responses.Histol Histopathol. 2010; 25: 1341-1354PubMed Google Scholar Eosinophil granules contain 4 cationic proteins: major basic proteins (MBP [MBP1 and PRG2]), eosinophil cationic protein (ECP [RNASE3]), eosinophil-derived neurotoxin (RNASE2), and eosinophil peroxidase (EPO).15Acharya K.R. Ackerman S.J. Eosinophil granule proteins: form and function.J Biol Chem. 2014; 289: 17406-17415Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar Eosinophil granules also store numerous cytokines, enzymes, and growth factors that promote airway remodeling and include the major mediator of airway remodeling, TGF-β, and MMPs. Fig 2 provides an overview of the eosinophil proteins involved in airway remodeling.32Ozdamar B. Bose R. Barrios-Rodiles M. Wang H.R. Zhang Y. Wrana J.L. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity.Science. 2005; 307: 1603-1609Crossref PubMed Scopus (740) Google Scholar, 33Hackett T.L. Warner S.M. Stefanowicz D. Shaheen F. Pechkovsky D.V. Murray L.A. et al.Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1.Am J Respir Crit Care Med. 2009; 180: 122-133Crossref PubMed Scopus (297) Google Scholar, 34Sun Z. Ji N. Ma Q. Zhu R. Chen Z. Wang Z. et al.Epithelial-mesenchymal transition in asthma airway remodeling is regulated by the IL-33/CD146 axis.Front Immunol. 2020; 11: 1598Crossref PubMed Scopus (30) Google Scholar, 35Chiarella E. Lombardo N. Lobello N. Aloisio A. Aragona T. Pelaia C. et al.Nasal polyposis: insights in epithelial-mesenchymal transition and differentiation of polyp mesenchymal stem cells.Int J Mol Sci. 2020; 21: 6878Crossref Scopus (5) Google Scholar,40Arjomandi M. Frelinger J. Donde A. Wong H. Yellamilli A. Raymond W. Secreted osteopontin is highly polymerized in human airways and fragmented in asthmatic airway secretions.PLoS One. 2011; 6e25678Crossref Scopus (10) Google Scholar, 41Delimpoura V. Bakakos P. Tseliou E. Bessa V. Hillas G. Simoes D.C. et al.Increased levels of osteopontin in sputum supernatant in severe refractory asthma.Thorax. 2010; 65: 782-786Crossref PubMed Scopus (0) Google Scholar, 42Kaartinen M.T. Pirhonen A. Linnala-Kankkunen A. Maenpaa P.H. Cross-linking of osteopontin by tissue transglutaminase increases its collagen binding properties.J Biol Chem. 1999; 274: 1729-1735Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 43Kohan M. Bader R. Puxeddu I. Levi-Schaffer F. Breuer R. Berkman N. Enhanced osteopontin expression in a murine model of allergen-induced airway remodelling.Clin Exp Allergy. 2007; 37: 1444-1454PubMed Google Scholar, 44Kohan M. Breuer R. Berkman N. Osteopontin induces airway remodeling and lung fibroblast activation in a murine model of asthma.Am J Respir Cell Mol Biol. 2009; 41: 290-296Crossref PubMed Scopus (0) Google Scholar, 45Trinh H.K.T. Nguyen T.V.T. Kim S.H. Cao T.B.T. Luu Q.Q. Kim S.H. et al.Osteopontin contributes to late-onset asthma phenotypes in adult asthma patients.Exp Mol Med. 2020; 52: 253-265Crossref Scopus (10) Google Scholar,52McBrien C.N. Menzies-Gow A. The biology of eosinophils and their role in asthma.Front Med (Lausanne). 2017; 4: 93Crossref PubMed Google Scholar, 53Al-Alwan L.A. Chang Y. Baglole C.J. Risse P.A. Halayko A.J. Martin J.G. et al.Autocrine-regulated airway smooth muscle cell migration is dependent on IL-17-induced growth-related oncogenes.J Allergy Clin Immunol. 2012; 130: 977-985.e6Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 54Atherton H.C. Jones G. Danahay H. IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation.Am J Physiol Lung Cell Mol Physiol. 2003; 285: L730-L739Crossref PubMed Google Scholar, 55Chu H.W. Balzar S. Seedorf G.J. Westcott J.Y. Trudeau J.B. Silkoff P. et al.Transforming growth factor-beta2 induces bronchial epithelial mucin expression in asthma.Am J Pathol. 2004; 165: 1097-1106Abstract Full Text Full Text PDF PubMed Google Scholar, 56Frossard N. Freund V. Advenier C. Nerve growth factor and its receptors in asthma and inflammation.Eur J Pharmacol. 2004; 500: 453-465Crossref PubMed Scopus (90) Google Scholar, 57Goldsmith A.M. Bentley J.K. Zhou L. Jia Y. Bitar K.N. Fingar D.C. et al.Transforming growth factor-beta induces airway smooth muscle hypertrophy.Am J Respir Cell Mol Biol. 2006; 34: 247-254Crossref PubMed Scopus (79) Google Scholar, 58Hayashi H. Kawakita A. Okazaki S. Yasutomi M. Murai H. Ohshima Y. IL-17A/F modulates fibrocyte functions in cooperation with CD40-mediated signaling.Inflammation. 2013; 36: 830-838Crossref PubMed Scopus (37) Google Scholar, 59Hernnas J. Sarnstrand B. Lindroth P. Peterson C.G. Venge P. Malmstrom A. Eosinophil cationic protein alters proteoglycan metabolism in human lung fibroblast cultures.Eur J Cell Biol. 1992; 59: 352-363PubMed Google Scholar, 60Hoshino M. Takahashi M. Aoike N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis.J Allergy Clin Immunol. 2001; 107: 295-301Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar, 61Ito I. Fixman E.D. Asai K. Yoshida M. Gounni A.S. Martin J.G. et al.Platelet-derived growth factor and transforming growth factor-beta modulate the expression of matrix metalloproteinases and migratory function of human airway smooth muscle cells.Clin Exp Allergy. 2009; 39: 1370-1380Crossref PubMed Scopus (56) Google Scholar, 62Malavia N.K. Mih J.D. Raub C.B. Dinh B.T. George S.C. IL-13 induces a bronchial epithelial phenotype that is profibrotic.Respir Res. 2008; 9: 27Crossref PubMed Scopus (0) Google Scholar, 63Michalik M. Pierzchalska M. Legutko A. Ura M. Ostaszewska A. Soja J. et al.Asthmatic bronchial fibroblasts demonstrate enhanced potential to differentiate into myofibroblasts in culture.Med Sci Monit. 2009; 15: BR194-201PubMed Google Scholar, 64Molet S. Hamid Q. Davoine F. Nutku E. Taha R. Page N. et al.IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines.J Allergy Clin Immunol. 2001; 108: 430-438Abstract Full Text Full Text PDF PubMed Scopus (796) Google Scholar, 65Nakao A. Sagara H. Setoguchi Y. Okada T. Okumura K. Ogawa H. et al.Expression of Smad7 in bronchial epithelial cells is inversely correlated to basement membrane thickness and airway hyperresponsiveness in patients with asthma.J Allergy Clin Immunol. 2002; 110: 873-878Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 66Shimizu S. Gabazza E.C. Hayashi T. Ido M. Adachi Y. Suzuki K. Thrombin stimulates the expression of PDGF in lung epithelial cells.Am J Physiol Lung Cell Mol Physiol. 2000; 279: L503-L510Crossref PubMed Google Scholar, 67Shimizu S. Gabazza E.C. Ogawa T. Tojima I. Hoshi E. Kouzaki H. et al.Role of thrombin in chronic rhinosinusitis-associated tissue remodeling.Am J Rhinol Allergy. 2011; 25: 7-11Crossref PubMed Scopus (42) Google Scholar, 68Thom